(E)-,(Z)-parallel preparative methods for stereodefined β,β-diaryl- and α,β-diaryl-α,β-unsaturated esters: Application to the stereocomplementary concise synthesis of zimelidine

Article abstract of DOI:10.1002/chem.201405150

Parallel and practical methods for the preparation of both (E)- and (Z)-β-aryl¹-β-aryl²-α,β-unsaturated esters 1 and (E)- and (Z)-α-aryl¹-β-aryl²-α,β-unsaturated esters 2 are described. These methods involve accessible, robust, stereocomplementary N-methylimidazole (NMI)-mediated enol tosylations (14 examples, 70-99 % yield), as well as stereoretentive Suzuki-Miyaura cross-couplings (36 examples, 64-99 % yield). The highlighted feature of the present protocol is the use of parallel and stereocomplementary approaches to obtain highly (E)- and (Z)-pure products 1 and 2 by utilizing sequential enol tosylations and cross-coupling reactions. An expeditious and parallel synthesis of (E)- and (Z)-zimelidine (3), which is a highly representative selective serotonin reuptake inhibitor (SSRI), was performed by utilizing the present methods.

Full text of DOI:10.1002/chem.201405150

DOI: 10.1002/chem.201405150
Full Paper
&
Synthesis Design
(E)-,(Z)-Parallel Preparative Methods for Stereodefined b,b-Diaryl-
and a,b-Diaryl-a,b-unsaturated Esters: Application to the
Stereocomplementary Concise Synthesis of Zimelidine
Yuichiro Ashida,[a] Yuka Sato,[a] Takeyuki Suzuki,[a] Kanako Ueno,[a] Ken-ichiro Kai,[a]
Hidefumi Nakatsuji,*[b] and Yoo Tanabe*[a]
Abstract: Parallel and practical methods for the preparation
of both (E)- and (Z)-b-aryl1-b-aryl2-a,b-unsaturated esters
1 and (E)- and (Z)-a-aryl1-b-aryl2-a,b-unsaturated esters 2 are
described. These methods involve accessible, robust, stereo-
complementary N-methylimidazole (NMI)-mediated enol to-
sylations (14 examples, 70–99% yield), as well as stereore-
tentive Suzuki–Miyaura cross-couplings (36 examples, 64–
99% yield). The highlighted feature of the present protocol
is the use of parallel and stereocomplementary approaches
to obtain highly (E)- and (Z)-pure products 1 and 2 by utiliz-
ing sequential enol tosylations and cross-coupling reactions.
An expeditious and parallel synthesis of (E)- and (Z)-zimeli-
dine (3), which is a highly representative selective serotonin
reuptake inhibitor (SSRI), was performed by utilizing the
present methods.
Introduction
Despite the reasonable demand for (E)- and (Z)-esters 1 and
2 for the synthesis of natural products, fine and supramole-
cules, and for process chemistry, stereoselective and general
preparative methods have not yet been fully established due
to the fundamental synthetic difficulty in differentiating be-
tween structurally similar diaryl (Ar1 and Ar2) moieties. A litera-
ture survey for the preparation of (E)- and (Z)-1 reveals that
1) Mizoroki–Heck reactions,[1] 2) a recent notable oxidative
Heck reaction sequence (Studer’s group),[2] and 3) an excellent
copper-catalyzed conjugate addition of ArB(OH)2 to alkynoates
(Yamamoto’s group)[3] are representative stereocontrolled
methods. A stereoselective preparative method of (E)- and (Z)-
2 with sufficient substrate generality, however, is more limited.
Sequential stereoretentive Suzuki–Miyaura cross-coupling with
(E)-b-chloro-a-iodo-a,b-unsaturated esters should also be in-
cluded as a successful example (Ogilvie’s group).[4] Condensa-
tion of ynolates with acetophenone is a useful method (Shin-
do’s group), but a sole example has been presented with mod-
erate stereoselectivity.[5]
The stereocontrolled preparation of ubiquitous (E)- and (Z)-a,b-
unsaturated esters is pivotal in organic syntheses because
these compounds serve as useful structural scaffolds for vari-
ous stereodefined olefins and conjugate (Michael) addition ac-
ceptors. Both (E)- and (Z)-b-aryl1-b-aryl2-a,b-unsaturated esters
1 and (E)- and (Z)-a-aryl1-b-aryl2-a,b-unsaturated esters 2 are
well-recognized synthetic building blocks among various a,b-
unsaturated esters (Figure 1).
Figure 1. Examples of (E)- and (Z)-b-aryl1-b-aryl2-a,b-unsaturated esters 1 and
(E)- and (Z)-a-aryl1-b-aryl2-a,b-unsaturated esters 2.
Consistent with our continued interest in finding a methodol-
ogy for the stereocomplementary preparation of (E)- and (Z)-
stereodefined a,b-unsaturated esters,[6] we disclose herein
a parallel preparative method for (E)- and (Z)-1 and (E)- and
(Z)-2. The present reaction sequence utilizes accessible and
robust N-methylimidazole (NMI)-mediated enol tosylations and
Suzuki–Miyaura cross-couplings, as depicted in Scheme 1. The
highlighted aspect of the present protocol is parallel and
stereocomplementary Approaches 1 and 2 to obtain highly (E)-
and (Z)-pure products 1 and 2 (or 2’) by accessible and robust
enol tosylations and cross-coupling reactions, which start from
readily available b-ketoesters 4 (or 4’) and 6 (or 6’), respective-
ly. The present dual-mode approach enhances the versatility of
[a] Y. Ashida, Y. Sato, T. Suzuki, K. Ueno, K.-i Kai, Prof. Dr. Y. Tanabe
Department of Chemistry, School of Science and Technology
Kwansei Gakuin University, 2-1 Gakuen, Sanda
Hyogo 669-1337 (Japan)
E-mail: tanabe@kwansei.ac.jp
[b] Dr. H. Nakatsuji
Graduate School of Engineering, Nagoya University Furo-cho
Chikusa, Nagoya 464-8603 (Japan)
E-mail: nakatsuji@nubio.nagoya-u.ac.jp
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201405150.
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a,b-unsaturated (cinnamic) ester
moiety.[11] 4) It should be noted
that all of these stereodefined
(E)- and (Z)-enol tosylates 5 are
novel compounds.
Subsequent (E)- and (Z)-
stereoretentive Suzuki–Miyaura
cross-couplings[12] with (E)- and
(Z)-5 were performed, as sum-
marized in Table 2. The salient
features are as follows: 1) Al-
though reported catalysis with
[Pd(OAc)(PCy3)][6b] produced dis-
appointing results (decomposi-
tion of (E)-5; a somewhat unde-
sirable isomerization for (Z)-5),
[Pd(dppb)Cl2]/KF or /K2CO3 catal-
ysis resulted from the reaction
with (E)-5, whereas [Pd(dppf)Cl2]/
K2CO3 catalysis produced fruitful
results for (Z)-5 in good to excel-
lent yield with consistent stereo-
retention. 2) In clear contrast to
the case of relevant aliphatic-
type substrates,[6b] which require
harsh conditions (reflux in DMF),
the present reaction proceeded
Scheme 1. Parallel and stereocomplementary syntheses of both (E)- and (Z)-diaryl (Ar1, Ar2) a,b-unsaturated esters
4 and 6. Ts=tosyl.
the project. To demonstrate the utility of the present method,
we describe an expeditious and parallel synthesis of (E)- and
(Z)-zimelidine (3),[7] which is a highly representative selective
serotonin reuptake inhibitor (SSRI; Figure 2).
smoothly under considerably milder conditions (608C in 2-
propanol) to give the corresponding (E)- and (Z)-esters 1 (Meth-
ods C-1 and D-1). 3) The parallel preparation mode was per-
formed to afford (E)-1b, (Z)-1b, (E)-1c, and (Z)-1c (Table 2, en-
tries 3–6 and 15–18). 4) Various substituents on Ar1 and/or Ar2,
such as p-Me, p-MeO, p-Cl, p-F, p-AcO o-Me, and o-Me, were
compatible (Table 2).
Table 1. The (E)- and (Z)-stereocomplementary enol tosylations of b-Ar1-
b-ketoesters 4.
Figure 2. Structures of (E)- and (Z)-zimelidine (3)synthesized by means of the
methodology described herein.
Results and Discussion
The initial (E)- and (Z)-stereocomplementary enol tosyla-
tions[8–10] of starting readily available b-ketoesters 4 were per-
formed by utilizing a conventional procedure with TsCl/NMI/
base, as listed in Table 1. The salient features are as follows:
1) (E)-enol tosylation proceeded in good to excellent yield, but
poor stereoselectivity, despite screening of a number of condi-
tions (amine and solvent; Method A-1). 2) In clear contrast, the
(Z)-enol tosylation exhibited nearly perfect stereoselectivity
(Method B-1). 3) Fortunately, (E)- and (Z)-enol tosylates 5 were
easily separated by column chromatography and/or recrystalli-
zation. This result markedly contrasted with that obtained
when using relevant aliphatic a,b-unsaturated esters,[6] which
was likely to be due to the intrinsically more stable (Z)-b-aryl-
Ketoesters 4
Method
Product
Yield
[%]
E/Z[a]
1
2
A-1
B-1
(E)-5a
(Z)-5a
73
70
60:40
2:>98
3
4
A-1
B-1
(E)-5b
(Z)-5b
96
80[b]
51:49
2:>98
5
6
A-1
B-1
(E)-5c
(Z)-5c
98
85[c]
59:41
2:>98
[a] Determined by 1H NMR spectroscopy of the crude products. [b] NaOH
was used instead of LiOH. [c] TsCl (2.0 equiv), LiOH (2.0 equiv), and NMI
(2.0 equiv) were used.
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nium cation aids (E)-enolate formation through
dipole–dipole repulsive interactions between the oxy
anion and ester function. In clear contrast, the (Z)-
stereoselective reaction proceeds through a chelation
mechanism to give (Z)-7a; the Li cation facilitates (Z)-
enolate formation.
Table 2. The (E)- and (Z)-stereoretentive Suzuki–Miyaura cross-coupling of b-Ar1-enol
tosylates 5.[a]
Successful results of subsequent (E)- and (Z)-stereo-
retentive Suzuki–Miyaura cross-coupling reactions
with enol tosylates (E)-7 and (Z)-7 are listed in
Table 4. Unfortunately, the aforementioned catalytic
reactions with [Pd(dppb)Cl2]/KF and [Pd(dppf)Cl2]/
K2CO3 could not be applied for the respective prepa-
ration of (E)-7 and (Z)-7; Under identical conditions,
Methods C-1 and D-1 resulted in low conversion
yields (ca. 20%). Several other catalytic reactions,
such as those with [Pd(PPh3)4], Pd(OAc)2/PCy3/base,
and [Pd(PPh3)2Cl2], gave similar disappointing results.
After standard screening procedures, to our delight,
the reaction with Pd(OAc)2/2-dicyclohexylphosphino-
2’,6’-dimethoxybiphenyl (SPhos)/iPr2NEt catalysis pro-
ceeded smoothly to give the desired products (E)-2
and (Z)-2.
The salient features are as follows: 1) For both (E)-7
and (Z)-7 substrates, the use of the Pd(OAc)2/Sphos/
iPr2NEt catalyst system produced fruitful results.
2) Excellent yields was obtained in almost all cases
examined (Table 4, entries 1–6, 9–16). 3) Notably,
almost perfect stereoretention was obtained in every
case examined. 4) Two sets of reactions with the (p-
Cl)C6H4B(OH)2 nucleophile (Ar2) and substrates con-
taining the (p-Cl)C6H4 group (Ar1) were concurrent
with further cross-couplings (Table 4, entries 7, 8, 17,
and 18). The structure of these byproducts was un-
Ar1
Ph
Substrate[b] Ar2
Method Product Yield [%] E/Z[c]
1
2
3
4
5
6
7
8
9
(E)-5a
(Z)-5a
(E)-5a
(Z)-5a
(E)-5a
(Z)-5a
(E)-5a
(Z)-5a
(E)-5a
(Z)-5a
(E)-5a
(Z)-5a
(E)-5a
(Z)-5a
(p-Me)C6H4 C-1
(E)-1a
(Z)-1a
(E)-1b
92 (88)[d] 95:5 (95:5)
D-1
(p-MeO)C6H4 C-1
D-1
88
83
2:>98
95:5
Ph
Ph
Ph
Ph
(Z)-1b 64
2:98
(p-Cl)C6H4
C-1
D-1
C-1
D-1
(E)-1c
(Z)-1c
(E)-1d
55 (88)[d] 98:2
77
82
11:89
96:4
(p-F)C6H4
(Z)-1d 80
13:87
98:2
10:90
96:4
10:90
96:4
10:90
14:86
90:10
3:97
(p-AcO)C6H4 C-1
(E)-1e
(Z)-1e
(E)-1 f
(Z)-1 f
(E)-1g
88
80
93
80
93
10
D-1
(o-CH3)C6H4 C-1
D-1
11 Ph
12
13 Ph
14
(o-Cl)C6H4
C-1
D-1
C-1
D-1
C-1
D-1
(Z)-1g 80
(Z)-1b 88[e]
15 (p-MeO)C6H4 (E)-5b
Ph
Ph
16
(Z)-5b
(E)-5b
(Z)-5b
(E)-1b
(Z)-1c
(E)-1c
91
17 (p-Cl)C6H4
87[f]
95
18
95:5
[a] dppb=1,4-bis(diphenylphosphino)butane, dppf=1,1’-bis(diphenylphosphino)ferro-
cene. [b] The E and Z purities were up to >98% based on the H NMR spectra. [c] De-
termined by 1H NMR spectroscopy of the crude products. [d] K2CO3 was used instead
of KF. [e] 5.0 equivalents of PhB(OH)2 were used. [f] 3.0 equivalents of PhB(OH)2 were
used.
1
Our next study focused on a parallel approach for the prepa-
ration of (E)- and (Z)-a-aryl1-b-aryl2-a,b-unsaturated esters 2.
The reported method of using a condensation reaction of yno-
lates with acetophenone produces a variety of tetrasubstituted
a,b-unsaturated esters,[5] wherein a sole specific example, (E)-
2a with E/Z=86:14, is produced. To the best of our knowl-
edge, there is no (E)- and (Z)-stereocomplementary method for
the preparation of 2 with sufficient substrate generality.
ambiguously determined based on 1H and 13C NMR spectrosco-
py, IR spectroscopy, and HRMS measurements. This conspicu-
ous problem was successfully resolved by using another cata-
lyst (see below). 5) The addition of H2O to the reaction system
dramatically affected the results; in the absence of H2O, the
yield decreased to about 20%. 6) Several substituents on Ar1
and/or Ar2, such as p-Me, p-MeO, and p-Cl, were compatible
(Table 4, entries 3–8 and 13–18). 7) Heterocyclic furan-3-yl and
3-thiophen-3-yl boronic acids served as suitable nucleophiles
(Table 4, entries 9–12).
Table 3 lists successful (E)- and (Z)-stereocomplementary
enol tosylations starting from b-ketoesters 6. Notably, refine-
ment of the reaction conditions led to highly satisfactory re-
sults (excellent yield and nearly perfect (E)- and (Z)-stereoselec-
tivity), replacement of MeCN with DMF was effective for the
preparation of (E)-7 (Method A-2), and the combined use of
TMEDA/LiCl displaced with NMI/LiOH was effective for (Z)-7
(Method B-2). Similar to the case of 5, all of these stereo-
defined (E)- and (Z)-enol tosylates 7 are novel compounds.
A plausible mechanism for the successful emergence of (E)-,
(Z)-enol tosylation stereoselectivity is depicted in Scheme 2,
wherein substrate 6a is exemplified. The addition of TsCl and
NMI forms key a highly reactive sulfonium ammonium salt, the
1
existence of which is supported by H NMR spectroscopic ana-
lysis.[6a] The (E)-stereoselective reaction proceeds through
a non-chelation pathway to give (E)-7a; the quaternary ammo-
Scheme 2. Mechanistic investigation into (E)- and (Z)-stereoselective enol
tosylation of 6a.
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Our synthetic approach and successful results are illustrated
in Scheme 3. The salient features are as follows: 1) Stereoselec-
tive enol tosylations of b-ketoesters 8a and 8b successfully
proceeded when using Methods A-1 and B-1, conditions [a]–
[d]. 2) Contrary to our expectations, Suzuki–Miyaura cross-cou-
pling with (3-Py)B(OH)2 with (E)-9 did not proceed (no reaction)
under identical conditions (Methods C-1 and D-1). Fortuitously,
the use of small amounts of H2O cosolvent resolved the prob-
lem for all four desired stereocomplementary reactions, condi-
tions [e]–[h], in excellent yield (79–91%) with almost perfect
stereoretention (E/Z= >97:3). 3) Despite the labile p-Br sub-
stituent, none of the four cross-couplings had serious side re-
actions, such as reduction or further couplings. 4) Compounds
(E)- and (Z)-3 were successfully obtained through the accessi-
ble reaction sequences, that is, DIBAL reduction, chlorination
with SOCl2/catalytic DMF, and final dimethylamination with an
aqueous solution of Me2NH, conditions [i] and [j]. Despite the
simple operation, undesirable isomerization between E and Z
did not occur. 5) Overall yields were 33% for (Z)-3 and 45% for
(E)-3 after each five parallel steps. Compared with extensive
studies on the synthesis for (E)- and (Z)-3,[13,14] which involved
MnO2 oxidation of allylic alcohol followed by reductive amina-
tion or dimethylamination, the present method is of highly
concise and orthogonal without tedious pH-dependent separa-
tion.
Table 3. The (E)- and (Z)-stereocomplementary enol tosylations of a-Ar1-
b-ketoesters 6.[a]
Ketoesters 6
Method
Product
Yield
[%]
E/Z[b]
1
2
3
4
5
6
7
8
A-2
B-2
A-2
B-2
A-2
B-2
A-2
B-2
(E)-7a
(Z)-7a
(E)-7b
(Z)-7b
(E)-7c
(Z)-7c
(E)-7d
(Z)-7d
94
93
98
99
98
99
92
98
>98:2
2:>98
>98:2
2:>98
>98:2
2:>98
>98:2
2:>98
6a
6b
6c
6d
Encouraged by the successful synthesis of (E)- and (Z)-3, we
[a] TMEDA=N,N,N’,N’-tetramethylethylenediamine. [b] Determined by
1H NMR spectroscopic analysis of the crude products.
reinvestigated two sets of cross-couplings by using
a
With this successful outcome
(Methods A-1, B-1, C-1, D-1) in
our hands, we next envisaged an
application for concise and paral-
lel stereocontrolled synthesis of
(E)- and (Z)-3. We referred fully
to the pioneering works estab-
lished by the groups of Bäckvall
and Hçgberg.[13,14]
The reported non-stereoselec-
tive method[13] for the synthesis
of 3 involved the following reac-
tion sequence: 1) addition of al-
lylmagnesium chloride with p-
bromophenyl 3-pyridyl ketone,
giving the tertiary allyl alcohol;
2) successive acid-promoted allyl
Scheme 3. Parallel and stereocomplementary syntheses of both (E)- and (Z)-3. Reagents and conditions: [a] TsCl
(1.5 equiv)/NMI (1.5 equiv)/Et3N (1.5 equiv)/N,N-dimethylacetamide (DMA), 20–258C, 1 h, 96%, E/Z=75:25. Pure
(E)-9 was isolated in 66% yield (column chromatography). [b] TsCl (2.0 equiv)/NMI (2.0 equiv)/NaOH (1.5 equiv)/
rearrangement, giving the allyl
chloride; and 3) final dimethyl-
amination. On the other hand, CH2Cl2, 20–258C, 2 h, 81%, E/Z=8:92, 81%. Pure (Z)-9 was isolated in 66% yield (washing with hexane). Notably,
stereoselective synthesis[14] was
the reaction with LiOH is very sluggish (only 29% yield). [c] TsCl (1.5 equiv)/NMI (1.5 equiv)/LiOH (1.5 equiv)/
CH2Cl2, 20–258C, 2 h, 72%, E/Z=2:>98. [d] Similar conditions to those given for [a], 92%, E/Z=67:33. Pure (Z)-10
was isolated in 62% yield (column chromatography). [e] (p-Br)C6H4B(OH)2 (1.05 equiv), [Pd(PPh3)2Cl2] (0.05 equiv),
K2CO3 (3.0 equiv), 2-propanol/H2O (3:1), 60–658C, 1 h, 89%, E/Z=>98:2. The use of [Pd(dppb)Cl2] gave about
performed proficiently by a rigor-
ous pH-controlled reductive ami-
nation procedure. Due to the dif- 35% conversion. [f] (p-Br)C6H4B(OH)2 (1.05 equiv), [Pd(PPh3)2Cl2] (0.05 equiv), K2CO3 (3.0 equiv), 2-propanol/H2O
(3:1), 60–658C, 1 h, 79%, E/Z=>98:2. [g] (3-Py)B(OH)2 (1.05 equiv), [Pd(dppf)Cl2] (0.05 equiv), K2CO3 (3.0 equiv), 2-
propanol/H2O (3:1), 60–658C, 81%, E/Z=2:>98. [h] Similar conditions to those given for [g] with (3-Py)B(OH)2,
ficulty of stereocontrol, and oxi-
dation as a side reaction, reduc-
81%, E/Z=97:3. [i] i) diisobutylaluminum hydride (DIBAL; 4.0 equiv)/THF, À788C, 0.5 h, 82%; ii) SOCl2 (1.5 equiv),
tive amination steps were re-
quired.
DMF (0.05 equiv)/CH2Cl2, 20–258C, successive treatment with an aqueous solution of Me2NH (10 equiv), 1 h, 91%,
E/Z=2:>98. [j] Similar conditions to those given for [i], overall 81%, E/Z=98/2.
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Conclusion
Table 4. The (E)- and (Z)-stereoretentive Suzuki–Miyaura cross-coupling of a-Ar1-enol
tosylates 7.
Preparative (E)- and (Z)-parallel methods have been
developed for a variety of stereodefined a,a-diaryl-
and a,b-diaryl-a,b-unsaturated esters. Robust enol
tosylation of b-ketoesters and Suzuki–Miyaura cross-
coupling with appropriate (subtle but laborious)
tuning of the catalysts improved the yield, stereo-
retention, and accessible reaction conditions. Suc-
cessful application to the concise and parallel stereo-
controlled synthesis of (E)- and (Z)-3 was also ach-
ieved. This method provides a new avenue for the
synthesis of these stereodefined a,a-diaryl- and a,b-
diaryl-a,b-unsaturated esters in the fields of natural
product synthesis and process chemistry.
Ar1
Ph
Substrate[a] Ar2
Method Product Yield [%] E/Z[b]
1
2
3
4
5
6
7
8
(E)-7a
(Z)-7a
(E)-7a
(Z)-7a
(E)-7a
(Z)-7a
(E)-7a
(Z)-7a
Ph
C-2
D-2
C-2
D-2
(E)-2a
(Z)-2a
(E)-2b
(Z)-2b
(E)-2c
(Z)-2c
(E)-2d
(Z)-2d
94
99
97
99
97
99
>98:2
2:>98
>98:2
2:>98
98:2
(p-Me)C6H4
(p-MeO)C6H4 C-2
D-2
(p-Cl)C6H4
2:>98
C-2
D-2
48 (10)[c] >98:2
41 (10)[d] 2:>98
Experimental Section
General
9
10
11
12
(E)-7a
(Z)-7a
(E)-7a
C-2
D-2
C-2
(E)-2e
(Z)-2e
(E)-2 f
92
96
94
>98:2
2:>98
>98:2
Starting b-ketoesters 4, 8a, and 8b were prepared by
the reported methods.[15,16] a,a-Diaryl-a,b-unsaturated
esters (E)- and (Z)-1a,[1j] (E)-[1j] and (Z)-[2] 1b, (E)- and (Z)-
1c,[2] (E)- and (Z)-1d[2] are known compounds. a,b-Diaryl-
a,b-unsaturated esters (E)- and (Z)-2a,[17] as well as (E)-
and (Z)-2b,[18] are known compounds. Starting b-ketoest-
ers 6a,[19] 6b,[20] 6c,[21] and 6d[19a] were prepared accord-
ing to reported methods.
(Z)-7a
(E)-7b
(Z)-7b
D-2
C-2
D-2
C-2
D-2
C-2
D-2
(Z)-2 f
(E)-2g
(Z)-2g
(E)-2h
(Z)-2h
(E)-2i
95
99
97
99
99
2:>98
>98:2
2:>98
>98:2
2:>98
13 (p-Me)C6H4
14
15 (p-MeO)C6H4 (E)-7c
16
17 (p-Cl)C6H4
18
Ph
Ph
Ph
(Z)-7c
(E)-7d
(Z)-7d
41 (50)[e] >98:2
58 (39)[f] 2:>98
Syntheses
(Z)-2i
Compound 6a:[19a] Methyl phenylacetate (15.02 g,
0.10 mol) and methyl acetate (22.22 g, 0.30 mol) in THF
(50 mL) were successively added dropwise to a stirred
suspension of tBuOK (8.42 g, 0.15 mol) in THF (50 mL) at
À788C under an argon atmosphere, and the mixture
was stirred at the same temperature for 2 h and at 40–
458C for 11 h. 1m HCl (ca. 100 mL) was added to the
mixture, which was extracted twice with AcOEt. The
combined organic phase was washed with water and
brine, dried (Na2SO4), and concentrated. The obtained
crude product was purified by distillation to give the de-
sired product (9.61 g, 51%) as a colorless oil. B.p. 108–
[a] The E and Z purities were up to >98% based on the 1H NMR spectra. [b] Deter-
mined by H NMR spectroscopy of the crude products.
1
110 8C/0.75 mmHg
(ref. [19]
92–968C/0.6 mmHg);
1H NMR: d=1.85 (s, 3H”3.5/10; enol form), 2.18 (s, 3H”
(p-Cl)C6H4B(OH)2 nucleophile with (E)-7a and (Z)-7a and
6.5/10; keto form), 3.69 (s, 3H”3.5/10; enol form), 3.76 (s, 3H”6.5/
10; keto form), 4.70 (s, 1H”6.5/10; keto form), 7.12–7.43 ppm (m,
5H); 13C NMR: d=19.6, 28.6, 51.6, 52.3, 65.4, 103.9, 126.9, 128.0,
128.1, 128.7, 129.2, 131.0, 132.5, 134.9, 168.8, 172.8, 173.9,
201.3 ppm; IR (neat): n˜max =2953, 1749, 1718, 1645, 1610, 1438,
a PhB(OH)2 nucleophile with acceptors (E)-7d and (Z)-7d,
which contained the (p-Cl)C6H4 group (see unsatisfactory cases
in Table 4, entries 7, 8, 17, and 18). Gratifyingly, as depicted in
Scheme 4, the reaction catalyzed by [Pd(PPh3)2Cl2]/K2CO3 in 2-
propanol/H2O (3:1) at 60–658C proceeded very smoothly to
give the desired products (E)-2d, (Z)-2d, (E)-2i, and (Z)-2i in
good yield with excellent stereoretention; the amounts of re-
spective undesirable further-coupled byproducts, (E)-2d-x, (Z)-
2d-x, (E)-2i-x, and (Z)-2i-x, decreased to trace amounts. The
present results contribute towards strengthening the substrate
generality of Methods C-2 and D-2. This outcome may be at-
tributed to milder catalysis with [Pd(PPh3)Cl2] than that of pow-
erful Pd(OAc)2/SPhos/base catalysis[15] with regard to this spe-
cific case.
1344, 1264 cmÀ1
.
Compound 6b:[20] Following the procedure for the preparation of
6a, the reaction of methyl p-tolylacetate (16.42 g, 0.10 mol) with
methyl acetate (22.22 g, 0.30 mol) and tBuOK (8.42 g, 0.15 mol)
gave the desired product (10.13 g, 49%) as a colorless oil. B.p. 83–
848C/0.53 mmHg; 1H NMR: d=1.85 (s, 3H”4.0/10; enol form),
2.17 (s, 3H”6.0/10; keto form), 2.35 (s, 3H”6.0/10; keto form),
2.36 (s, 3H”4.0/10; enol form), 3.69 (s, 3H”4.0/10; enol form),
3.75 (s, 3H”6.0/10; keto form), 4.66 (s, 1H”6.0/10; keto form),
7.02–7.25 ppm (m, 4H); 13C NMR: d=19.6, 20.9, 20.9, 28.4, 51.5,
52.2, 64.9, 103.6, 128.7, 129.0, 129.4, 130.8, 131.9, 137.9, 168.9,
Chem. Eur. J. 2015, 21, 5934 – 5945
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Full Paper
General procedure for (E)-, (Z)-stereocomplementary enol
tosylations
Method A-1: TsCl (2.86 g, 15 mmol) in MeCN (10 mL) was added to
a stirred solution of a b-ketoester 4 (10 mmol), NMI (1.23 g,
15 mmol), and Et3N (1.52 g, 15 mmol) in MeCN (10 mL) at 20–258C
under an argon atmosphere, followed by stirring for 1 h. Water
was added to the stirred mixture, which was extracted with EtOAc.
The organic phase was washed with 1m HCl and brine, dried
(Na2SO4), and concentrated. The obtained crude product was puri-
fied by column chromatography on silica gel (hexane/AcOEt=
20:1–5:1) or recrystallization to give the corresponding desired
product (E)-5.
Method B-1: TsCl (2.86 g, 15 mmol) in CH2Cl2 (10 mL) was added to
a
stirred solution of b-ketoester 4 (10 mmol), NMI (1.23 g,
15 mmol) and LiOH (359 mg, 15 mmol) in CH2Cl2 (10 mL) at 0–58C
under an argon atmosphere. The mixture was stirred at same tem-
perature for 1 h and at 20–258C for 1 h. A similar workup to that
of Method A-1 gave the corresponding desired product (Z)-5.
Method A-2: TsCl (286 mg, 1.50 mmol) in DMF (1.0 mL) was added
to a stirred solution of b-ketoester 6 (1.00 mmol), NMI (124 mg,
1.50 mmol), and Et3N (152 mg, 1.50 mmol) in DMF (1.0 mL) at 0–
58C and the mixture was stirred at the same temperature for 1 h
and at 20–258C for 1 h. A large amount of water was added to the
mixture, which was extracted twice with AcOEt. The combined or-
ganic phase was washed with large amounts of water, a saturated
aqueous solution of NaHCO3, and brine; dried (Na2SO4); and con-
centrated. The obtained crude product was purified by column
chromatography on silica gel (hexane/AcOEt=50:1–20:1) to give
the corresponding desired product (E)-7.
Scheme 4. Refinement for catalysis with the p-Cl-substituted nucleophile
and substrate by using Methods C-2 and D-2.
Method B-2: TsCl (286 mg, 1.50 mmol) in CH3CN (1.0 mL) was added
to a stirred solution of b-ketoester 6 (1.00 mmol), TMEDA (258 mg,
1.50 mmol), and LiCl (64 mg, 1.50 mmol) in CH3CN (1.0 mL) at 0–
58C and the mixture was stirred at the same temperature for 1 h
and at 20–258C for 1 h. A large amount of water (large amount)
was added to the mixture, which was extracted twice with AcOEt.
The combined organic phase was washed with large amounts of
water, a saturated aqueous solution of NaHCO3, and brine; dried
(Na2SO4); and concentrated. The obtained crude product was puri-
fied by column chromatography on silica gel (hexane/AcOEt=
50:1–20:1) to give the corresponding desired product (Z)-7.
172.8, 173.8, 201.4 ppm; IR (neat): n˜max =2953, 1717, 1644, 1514,
1439, 1340, 1264, 1228 cmÀ1
.
Compound 6c:[21] Following the procedure for the preparation of
6a, the reaction of methyl p-methoxyphenylacetate (18.02 g,
0.10 mol) with methyl acetate (22.22 g, 0.30 mol) and tBuOK
(8.42 g, 0.15 mol) gave the desired product (9.56 g, 43%) as a color-
1
less oil. B.p. 93–958C/0.56 mmHg; H NMR: d=1.85 (s, 3H”3.0/10;
enol form), 2.17 (s, 3H”7.0/10; keto form), 3.69 (s, 3H”3.0/10;
enol form), 3.75 (s, 3H”7.0/10; keto form), 3.81 (s, 3H”7.0/10;
keto form), 3.82 (s, 3H”3.0/10; enol form), 4.65 (s, 1H”7.0/10;
keto form), 6.85–7.29 ppm (m, 4H); 13C NMR: d=19.6, 28.5, 51.6,
52.3, 55.0, 55.1, 64.5, 103.3, 113.3, 113.4, 114.2, 124.5, 127.1, 130.3,
Compound (E)-5a: Colorless crystals; m.p. 79–818C; 1H NMR
(300 MHz, CDCl3): d=2.41 (s, 3H), 3.62 (s, 3H), 6.08 (s, 1H), 7.18–
7.38 (m, 7H), 7.66 ppm (d, J=8.3 Hz, 2H); 13C NMR (75 MHz, CDCl3):
d=21.6, 51.6, 111.3, 127.7, 128.2, 129.2, 129.7, 130.4, 131.7, 132.9,
145.5, 159.6, 164.9 ppm; IR (neat): n˜max =3058, 2952, 1730, 1645,
1597, 1435, 1377, 1193, 1038, 806cmÀ1; HRMS (ESI): m/z calcd for
C17H16O5S [M+Na]+: 355.0616; found: 355.0620.
132.1, 158.5, 159.4, 169.2, 173.0, 174.0, 201.7 ppm; IR (neat): n˜max
2954, 2839, 1714, 1609, 1512, 1441, 1355, 1247 cmÀ1
=
.
Compound (Z)-5a: Colorless crystals; m.p. 103–1058C; 1H NMR
(300 MHz, CDCl3): d=2.40 (s, 3H), 3.69 (s, 3H), 6.11 (s, 1H), 7.17–
7.45 (m, 7H), 7.72 ppm (d, J=8.3 Hz, 2H); 13C NMR (75 MHz, CDCl3):
d=21.6, 51.6, 110.3, 126.9, 128.4, 129.4, 130.7, 133.0, 133.4, 145.2,
155.7, 163.8 ppm; IR (neat): n˜max =1732, 1646, 1384, 1270, 1178,
Compound 6d: Following the procedure for the preparation of
6a, the reaction of methyl p-chlorophenylacetate (18.46 g,
0.10 mol) with methyl acetate (22.22 g, 0.30 mol) and tBuOK
(8.42 g, 0.15 mol) gave the desired product (8.84 g, 39%) as a color-
763 cmÀ1
.
1
less oil. B.p. 90–928C/0.49 mmHg; H NMR: d=1.85 (s, 3H”8.0/10;
1
enol form), 2.20 (s, 3H”2.0/10; keto form), 3.69 (s, 3H”8.0/10;
enol form), 3.76 (s, 3H”2.0/10; keto form), 4.69 (s, 1H”2.0/10;
keto form), 7.07–7.39 ppm (m, 4H); 13C NMR: d=19.6, 28.6, 51.6,
52.4, 64.4, 102.8, 128.2, 128.8, 130.6, 130.9, 132.4, 133.4, 134.2,
168,4, 172.4, 174.1, 200.5 ppm; IR (neat): n˜max =2953, 1718, 1645,
1611, 1492, 1340, 1266, 1224 cmÀ1; HRMS (ESI): m/z calcd for
C11H11O3Cl [M+Na]+: 249.0294; found: 249.0303.
Compound (E)-5b: Pale yellow oil; H NMR (300 MHz, CDCl3): d=
2.42 (s, 3H), 3.64 (s, 3H), 3.80 (s, 3H), 5.96 (s, 1H), 6.76 (d, J=
8.9 Hz, 2H), 7.24 (d, J=7.9 Hz, 2H), 7.32 (d, J=8.9 Hz, 2H),
7.67 ppm (d, J=8.6 Hz, 2H); 13C NMR (75 MHz, CDCl3): d=21.6,
51.6, 55.3, 110.0, 113.1, 123.9, 128.3, 129.7, 131.1, 145.4, 159.7,
161.4, 165.2 ppm; IR (neat): n˜max =2954, 2841, 1727, 1636, 1606,
1511, 1375, 1176, 1032, 779 cmÀ1
.
Chem. Eur. J. 2015, 21, 5934 – 5945
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5939 ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
1
Compound (Z)-5b: Pale yellow oil; H NMR (300 MHz, CDCl3): d=
124.5, 127.3, 127.7, 129.3, 130.7, 131.4, 132.9, 133.3, 145.0, 154.7,
166.6 ppm; IR (neat): n˜max =1717, 1639, 1595, 1491, 1224, 1195,
1178, 1156 cmÀ1; HRMS (ESI): m/z calcd for C18H17O5S [M+Na]+:
403.0383; found: 403.0377.
2.42 (s, 3H), 3.66 (s, 3H), 3.81 (s, 3H), 6.01 (s, 1H), 6.78 (d, J=
8.9 Hz, 2H), 7.25 (d, J=8.0 Hz, 2H), 7.38 (d, J=8.9 Hz, 2H),
7.75 ppm (d, J=8.6 Hz, 2H); 13C NMR (75 MHz, CDCl3): d=21.5,
51.4, 55.3, 108.1, 113.8, 125.2, 128.4, 128.6, 129.4, 133.5, 145.1,
155.6, 161.7, 163.9 ppm; IR (neat): n˜max =3019, 2952, 1730, 1645,
1605, 1511, 1257, 1176, 1037, 909, 731 cmÀ1; HRMS (ESI): m/z calcd
for C18H18O6S [M+Na]+: 385.0722; found: 385.0717.
1
Compound (Z)-7d: Colorless crystals; m.p. 75–768C; H NMR: d=
1.98 (s, 3H), 2.47 (s, 3H), 3.57 (s, 3H), 7.14–7.21 (m, 2H), 7.30–7.42
(m, 4H), 7.85–7.92 ppm (m, 2H); 13C NMR: d=19.1, 21.7, 52.2,
125.2, 128.1, 128.8, 129.8, 130.6, 132.2, 133.5, 134.4, 145.4, 150.3,
165.3 ppm; IR (neat): n˜max =1721, 1652, 1595, 1491, 1346, 1313,
1
Compound (E)-5c: Pale yellow oil; H NMR (300 MHz, CDCl3): d=
1223, 1194 cmÀ1
.
2.43 (s, 3H), 3.64 (s, 3H), 6.07 (s, 1H), 7.17–7.31 (m, 6H), 7.65 ppm
(d, J=8.3 Hz, 2H); 13C NMR (75 MHz, CDCl3): d=21.6, 51.7, 111.9,
127.9, 128.2, 129.8, 130.1, 130.6, 132.7, 136.6, 145.8, 158.4,
164.7 ppm; IR (neat): n˜max =3027, 2852, 1730, 1646, 1380, 1217,
General procedure for (E)-, (Z)-stereoretentive Suzuki–
Miyaura cross-couplings
1193, 1036, 755 cmÀ1
.
Compound (Z)-5c: Pale yellow crystals; m.p. 73–758C; 1H NMR
(300 MHz, CDCl3): d=2.43 (s, 3H), 3.68 (s, 3H), 6.09 (s, 1H), 7.20–
7.29 (m, 4H), 7.37 (d, J=8.9 Hz, 2H), 7.74 ppm (d, J=8.3 Hz, 2H);
13C NMR (75 MHz, CDCl3): d=21.5, 51.4, 55.3, 108.1, 113.8, 125.2,
128.4, 128.6, 129.4, 133.5, 145.1, 155.6, 161.7, 163.9 ppm; IR (neat):
n˜max =1732, 1646, 1435, 1268, 1178, 1038, 928, 765 cmÀ1; HRMS
(ESI): m/z calcd for C17H15ClO5S [M+Na]+: 389.0226; found:
389.0238.
Method C-1: A suspension of an enol tosylate (E)-5 (0.50 mmol),
ArB(OH)2 (0.75 mmol), [Pd(dppb)Cl2] (15 mg, 0.025 mmol), and KF
(87 mg, 1.5 mmol) in 2-propanol (3.0 mL) was stirred at 60–658C
under an argon atmosphere for 2 h. After cooling, water was
added to the mixture, which was extracted twice with AcOEt. The
combined organic phase was washed with water and brine, dried
(Na2SO4), and concentrated. The obtained crude product was puri-
fied by column chromatography on silica gel (hexane/diethyl
ether=100:1–20:1) to give the corresponding desired product
(E)-1.
1
Compound (E)-7a: Colorless crystals; m.p. 71–728C; H NMR: d=
2.37 (s, 3H), 2.53 (s, 3H), 3.70 (s, 3H), 6.96–7.31 ppm (m, 9H);
13C NMR: d=19.9, 21.4, 52.2, 125.9, 127.3, 127.5, 127.7, 129.3,
129.3, 132.7, 133.0, 144.7, 153.6, 167.2 ppm; IR (neat): n˜max =2359,
1715, 1639, 1433, 1361, 1193, 1154, 1064 cmÀ1; HRMS (ESI): m/z
calcd for C18H18O5S [M+Na]+: 369.0773; found: 369.0779.
Method D-1: A suspension of enol tosylate (Z)-5 (0.50 mmol),
ArB(OH)2 (0.75 mmol), [Pd(dppf)Cl2] (18 mg, 0.025 mmol), and
K2CO3 (207 mg, 1.50 mol) in 2-propanol (3.0 mL) was stirred at 60–
658C under an argon atmosphere for 2 h. After cooling, water was
added to the mixture, which was extracted twice with AcOEt. The
combined organic phase was washed with water and brine, dried
(Na2SO4), and concentrated. The obtained crude product was puri-
fied by column chromatography on silica gel (hexane/diethyl
ether=100:1–20:1) to give the corresponding desired product
(Z)-1.
1
Compound (Z)-7a: Colorless oil; H NMR: d=1.98 (s, 3H), 2.43 (s,
3H), 3.53 (s, 3H), 7.17–7.40 (m, 7H), 7.85–7.92 ppm (m, 7H);
13C NMR: d=18.7, 21.4, 51.8, 126.2, 127.9, 128.1, 128.3, 128.9,
129.6, 133.2, 133.5, 145.2, 149.3, 165.4 ppm; IR (neat): n˜max =1727,
1597, 1434, 1371, 1226, 1195, 1092, 1057cmÀ1
.
1
Compound (E)-7b: Colorless crystals; m.p. 79–808C; H NMR: d=
2.30 (s, 3H), 2.36 (s, 3H), 2.50 (s, 3H), 3.68 (s, 3H), 6.84–6.91 (m,
2H), 6.91–6.98 (m, 2H), 7.01–7.08 (m, 2H), 7.26–7.32 ppm (m, 2H);
13C NMR: d=20.0, 21.1, 21.5, 52.2, 125.9, 127.6, 128.4, 129.1, 129.2,
130.0, 133.0, 137.1, 144.6, 153.3, 167.4 ppm; IR (neat): n˜max =2951,
1716, 1645, 1352, 1291, 1194, 1178, 1155 cmÀ1; HRMS (ESI): m/z
calcd for C19H20O5S [M+Na]+: 383.0929; found: 383.0943.
Method C-2: A suspension of enol tosylate (E)-7 (0.50 mmol),
ArB(OH)2 (0.75 mmol), iPr2NEt (194 mg, 1.50 mol), Pd(OAc)2 (6 mg,
0.025 mmol), and SPhos (20 mg, 0.05 mmol) in toluene (0.7 mL)/
water (3.3 mL) was stirred at 80–858C under an argon atmosphere
for 2 h. After cooling, water was added to the mixture, which was
extracted twice with AcOEt. The combined organic phase was
washed with water and brine, dried (Na2SO4), and concentrated.
The obtained crude product was purified by column chromatogra-
phy on silica gel (hexane/diethyl ether=200:1–100:1) to give the
corresponding desired product (E)-2.
1
Compound (Z)-7b: Colorless crystals; m.p. 95–968C; H NMR: d=
2.00 (s, 3H), 2.35 (s, 3H), 2.46 (s, 3H), 3.55 (s, 3H), 7.08–7.14 (m,
2H), 7.14–7.20 (m, 2H), 7.34–7.40 (m, 2H), 7.86–7.92 ppm (m, 2H);
13C NMR: d=18.8, 21.1, 21.5, 51.9, 126.2, 128.0, 128.9, 129.1, 129.7,
130.6, 133.5, 138.1, 145.2, 149.2, 165.8 ppm; IR (neat): n˜max =1724,
1431, 1365, 1304, 1225, 1193, 1178, 1057 cmÀ1
.
Compound (E)-7c: Pale yellow crystals; m.p. 90–918C; 1H NMR:
d=2.38 (s, 3H), 2.49 (s, 3H), 3.71 (s, 3H), 3.79 (s, 3H), 6.64–6.70 (m,
2H), 6.88–6.95 (m, 2H), 7.04–7.10 (m, 2H), 7.30–7.36 ppm (m, 2H);
13C NMR: d=20.1, 21.5, 52.2, 55.0, 113.1, 125.1, 125.6, 127.6, 129.2,
130.5, 132.9, 144.6, 152.9, 158.8, 167.6 ppm; IR (neat): n˜max =2954,
1715, 1607, 1513, 1435, 1345, 1224, 1177 cmÀ1; HRMS (ESI): m/z
calcd for C19H20O6S [M+Na]+: 399.0878; found: 399.0876.
Method D-2: A suspension of enol tosylate (Z)-7 (0.50 mmol),
ArB(OH)2 (0.75 mmol), iPr2NEt (194 mg, 1.5 mol), Pd(OAc)2 (6 mg,
0.025 mmol), and SPhos (20 mg, 0.05 mmol) in toluene (0.7 mL)/
water (3.3 mL) was stirred at 80–858C under an argon atmosphere
for 2 h. After cooling, water was added to the mixture, which was
extracted twice with AcOEt. The combined organic phase was
washed with water and brine, dried (Na2SO4), and concentrated.
The obtained crude product was purified by column chromatogra-
phy on silica gel (hexane/diethyl ether=200:1–100:1) to give the
corresponding desired product (Z)-2.
Compound (Z)-7c: Pale yellow crystals; m.p. 67–688C; 1H NMR:
d=1.99 (s, 3H), 2.44 (s, 3H), 3.55 (s, 3H), 3.78 (s, 3H), 6.84–6.92 (m,
2H), 7.10–7.19 (m, 2H), 7.33–7.41 (m, 2H), 7.84–7.91 ppm (m, 2H);
13C NMR: d=18.7, 21.4, 51.8, 55.0, 113.8, 125.6, 125.9, 127.9, 129.6,
130.2, 133.4, 145.2, 148.8, 159.3, 165.9 ppm; IR (neat): n˜max =1725,
1
Compound (E)-1a:[1j] Pale yellow oil; H NMR (300 MHz, CDCl3): d=
2.35 (s, 3H), 3.60 (s, 3H), 6.35 (s, 1H), 7.12 (d, J=7.9 Hz, 2H), 7.15–
7.23 (m, 2H), 7.32–7.43 ppm (m, 3H); 13C NMR (75 MHz, CDCl3): d=
21.1, 51.1, 115.8, 127.7, 128.0, 128.2, 129.0, 137.9, 138.9, 139.6,
157.0, 166.4 ppm; IR (neat): n˜max =3022, 2948, 1719, 1608, 1433,
1608, 1512, 1435, 1366, 1282, 1092, 1052 cmÀ1
.
Compound (E)-7d: Pale yellow crystals; m.p. 80–818C; 1H NMR:
d=2.41 (s, 3H), 2.55 (s, 3H), 3.70 (s, 3H), 6.88–6.94 (m, 2H), 7.05–
7.15 (m, 4H), 7.28–7.34 ppm (m, 2H); 13C NMR: d=20.1, 21.3, 52.1,
1267, 1164, 910, 756 cmÀ1
.
Chem. Eur. J. 2015, 21, 5934 – 5945
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5940 ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
1
Compound (Z)-1a: [1j]: Colorless oil; H NMR (300 MHz, CDCl3): d=
166.6 ppm; IR (neat): n˜max =3058, 1722, 1616, 1432, 1359, 1257,
2.39 (s, 3H), 3.63 (s, 3H), 6.32 (s, 1H), 7.10 (d, J=7.9 Hz, 2H), 7.19
(d, J=7.9 Hz, 2H), 7.27–7.42 ppm (m, 5H); 13C NMR (75 MHz,
CDCl3): d=21.3, 51.1, 116.4, 128.3, 128.3, 128.6, 129.1, 129.3, 135.7,
138.0, 141.1, 157.3, 166.4 ppm; IR (neat): n˜max =3024, 2949, 1725,
1610, 1508, 1362, 1266, 1165, 722 cmÀ1; HRMS (ESI): m/z calcd for
C17H16O2 [M+Na]+: 275.1048; found: 275.1046.
1164, 1033, 909, 728 cmÀ1
1
Compound (Z)-1 f: Colorless oil; H NMR (300 MHz, CDCl3): d=2.07
(s, 3H), 3.58 (s, 3H), 6.53 (s, 1H), 7.02–7.11 (m, 1H), 7.17–7.40 ppm
(m, 8H); 13C NMR (75 MHz, CDCl3): d=19.5, 51.2, 116.9, 125.4,
127.4, 127.8, 128.3, 128.5, 129.5, 129.9, 135.3, 138.4, 139.2, 156.5,
166.0 ppm; IR (neat): n˜max =3059, 2949, 1721, 1618, 1433, 1359,
1264, 1165, 1016, 908, 729 cmÀ1; HRMS (ESI): m/z calcd for C17H16O2
[M+Na]+: 275.1048; found: 275.1071.
Compound (E)-1b:[1j] Brown colored oil; H NMR (300 MHz, CDCl3):
1
d=3.59 (s, 3H), 3.81 (s, 3H), 6.31 (s, 1H), 6.84 (d, J=8.9 Hz, 2H),
7.15–7.27 (m, 4H), 7.35–7.43 ppm (m, 5H); 13C NMR (75 MHz,
CDCl3): d=51.1, 55.3, 113.7, 114.6, 127.8, 128.0, 129.0, 129.7, 133.0,
139.0, 156.8, 160.8, 166.5 ppm; IR (neat): n˜max =2950, 1717, 1607,
1
Compound (E)-1g: Colorless oil; H NMR (300 MHz, CDCl3): d=3.66
(s, 3H), 6.10 (s, 1H), 7.19–7.40 ppm (m, 9H); 13C NMR (75 MHz,
CDCl3): d=51.3, 121.0, 126.6, 127.6, 128.5, 129.0, 129.5, 130.1,
130.9, 132.7, 137.8, 140.7, 154.0, 166.2 ppm; IR (neat): n˜max =3060,
1724, 1621, 1433, 1360, 1245, 1166, 909, 728 cmÀ1; HRMS (ESI): m/z
calcd for C16H13ClO2 [M+Na]+: 295.0502; found: 295.0567.
1509, 1248, 1166, 773 cmÀ1
.
Compound (Z)-1b:[2] Colorless oil; 1H NMR (300 MHz, CDCl3): d=
3.64 (s, 3H), 3.84 (s, 3H), 6.27 (s, 1H), 6.91 (d, J=8.6 Hz, 2H), 7.16
(d, J=8.6 Hz, 2H), 7.23–7.42 ppm (m, 5H); 13C NMR (75 MHz,
CDCl3): d=51.2, 55.2, 113.2, 116.2, 128.3, 128.5, 129.3, 130.9, 130.9,
141.5, 157.0, 159.7, 166.6 ppm; IR (neat): n˜max =3019, 2952, 1717,
1607, 1509, 1247, 1167, 908, 755 cmÀ1; HRMS (ESI): m/z calcd for
C17H16O3 [M+Na]+: 291.0997; found: 291.1019.
1
Compound (Z)-1g: Pale yellow oil; H NMR (300 MHz, CDCl3): d=
3.60 (s, 3H), 6.55 (s, 1H), 7.12–7.21 (m, 1H), 7.23–7.40 (m, 7H),
7.40–7.49 ppm (m, 1H); 13C NMR (75 MHz, CDCl3): d=51.3, 118.1,
126.4, 127.3, 128.6, 129.1, 129.4, 129.6, 130.0, 132.5, 137.8, 138.5,
153.7, 165.6 ppm; IR (neat): n˜max =3060, 2949, 1723, 1623, 1432,
1
Compound (E)-1c:[2]: Pale yellow oil; H NMR (300 MHz, CDCl3): d=
1358, 1268, 1165, 1035, 909, 730 cmÀ1
.
3.61 (s, 3H), 6.34 (s, 1H), 7.14–7.32 (m, 6H), 7.35–7.45 ppm (m, 3H);
13C NMR (75 MHz, CDCl3): d=51.2, 117.1, 127.9, 128.4, 128.6, 129.0,
129.5, 135.5, 138.3, 139.2, 155.6, 166.1 ppm; IR (neat): n˜max =3019,
1716, 1617, 1488, 1434, 1215, 1168, 907, 732 cmÀ1; HRMS (ESI): m/z
calcd for C16H13ClO2 [M+Na]+: 295.0502; found: 295.0582.
Compound (Z)-1c:[2] Colorless oil; 1H NMR (300 MHz, CDCl3): d=
3.62 (s, 3H), 6.37 (s, 1H), 7.15 (d, J=8.6 Hz, 2H), 7.22–7.40 ppm (m,
7H); 13C NMR (75 MHz, CDCl3): d=51.2, 117.1, 128.1, 128.2, 128.4,
1
Compound (E)-2a:[17] Pale yellow oil; H NMR: d=2.36 (s, 3H), 3.76
(s, 3H), 6.95–7.18 ppm (m, 10H); 13C NMR: d=23.2, 51.9, 126.8,
127.0, 127.7, 127.8, 128.4, 129.8, 131.6, 137.1, 141.8, 144.6,
169.8 ppm; IR (neat): n˜max =2950, 1719, 1599, 1491, 1433, 1375,
1304, 1250 cmÀ1
.
1
Compound (Z)-2a:[17] Pale yellow oil; H NMR: d=2.05 (s, 3H), 3.43
(s, 3H), 7.29–7.44 ppm (m, 10H); 13C NMR: d=22.2, 51.5, 126.8,
127.5, 128.1, 128.3, 129.1, 132.5, 137.1, 142.8, 143.9, 169.6 ppm; IR
129.6, 130.5, 134.2, 137.1, 140.3, 155.8, 166.1 ppm; IR (neat): n˜max
3021, 2950, 1718, 1617, 1488, 1272, 1167, 908, 756 cmÀ1
=
(neat): n˜max =2941, 1719, 1491, 1433, 1375, 1304, 1252, 1210 cmÀ1
.
.
[2]
1
1
Compound (E)-2b:[18] Pale yellow oil; H NMR: d=2.24 (s, 3H), 2.34
(s, 3H), 3.77 (s, 3H), 6.88–6.95 (m, 3H), 6.99–7.04 (m, 2H), 7.06–
7.16 ppm (m, 4H); 13C NMR: d=21.0, 23.2, 51.9, 126.7, 127.8, 128.4,
128.5, 129.9, 131.3, 136.7, 137.4, 138.8, 144.5, 169.9 ppm; IR (neat):
Compound (E)-1d: Colorless oil; H NMR (300 MHz, CDCl3): d=
3.61 (s, 3H), 6.31 (s, 1H), 7.00 (t, J=8.9 Hz, 2H), 7.15–7.22 (m, 2H),
7.24–7.30 (m, 2H), 7.39 ppm (t, J=3.1 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d=51.2, 115.2, 115.5, 116.6, 127.9, 128.3, 129.0, 130.1, 130.2,
138.6, 155.8, 166.2 ppm; IR (neat): n˜max =3021, 2950, 1718, 1600,
1507, 1434, 1362, 1267, 1166, 909, 732 cmÀ1; HRMS (ESI): m/z calcd
for C16H13FO2 [M+Na]+: 279.0797; found: 279.0827.
n˜max =2949, 2859, 1719, 1624, 1509, 1433, 1320, 1250 cmÀ1
.
1
Compound (Z)-2b:[18] Pale yellow oil; H NMR: d=2.03 (s, 3H), 2.36
(s, 3H), 3.46 (s, 3H), 7.05–7.28 (m, 5H), 7.29–7.43 ppm (m, 4H);
13C NMR: d=21.2, 22.2, 51.6, 126.8, 127.4, 128.3, 128.3, 128.9,
129.2, 129.8, 137.3, 139.8, 143.9, 169.8 ppm; IR (neat): n˜max =2950,
Compound (Z)-1d;[2] Pale yellow oil; H NMR (300 MHz, CDCl3): d=
1
3.63 (s, 3H), 6.36 (s, 1H), 7.07 (t, J=8.6 Hz, 2H), 7.20 (dd, J=5.5,
8.3 Hz, 2H), 7.24–7.42 ppm (m, 5H); 13C NMR (75 MHz, CDCl3): d=
51.2, 114.7, 115.0, 117.0, 128.2, 128.4, 129.5, 131.0, 131.1, 140.7,
156.0, 166.2 ppm; IR (neat): n˜max =3019, 1713, 1602, 1509, 1215,
1721, 1626, 1512, 1433, 1375, 1304, 1250 cmÀ1
.
Compound (E)-2c: Colorless crystals; m.p. 69–708C; 1H NMR: d=
2.34 (s, 3H), 3.73 (s, 3H), 3.77 (s, 3H), 6.60–6.70 (m, 2H), 6.88–
7.18 ppm (m, 7H); 13C NMR: d=23.1, 51.9, 55.0, 113.2, 126.7, 127.8,
129.8, 129.9, 131.0, 133.9, 137.5, 144.1, 158.5, 170.1 ppm; IR (neat):
n˜max =2951, 1719, 1609, 1510, 1458, 1433, 1248, 1208 cmÀ1; HRMS
(ESI): m/z calcd for C18H18O3 [M+Na]+: 305.1154; found: 305.1157.
Compound (Z)-2c: Colorless crystals; m.p. 96–978C; 1H NMR: d=
2.03 (s, 3H), 3.47 (s, 3H), 3.83 (s, 3H), 6.81–6.94 (m, 2H), 7.17–
7.42 ppm (m, 7H); 13C NMR: d=22.2, 51.7, 55.2, 113.6, 127.5, 128.2,
1172, 908, 753 cmÀ1
.
Compound (E)-1e: Pale yellow crystals; m.p. 97–988C; 1H NMR
(300 MHz, CDCl3) d=2.60 (s, 3H), 3.63 (s, 3H), 6.42 (s, 1H), 7.16–
7.24 (m, 2H), 7.00 (t, J=8.9 Hz, 2H), 7.34–7.46 (m, 5H), 7.39 ppm
(d, J=8.3 Hz, 2H); 13C NMR (75 MHz, CDCl3) d=26.6, 51.3, 118.6,
128.0, 128.2, 128.4, 129.0, 137.4, 138.0, 145.2, 155.4, 166.0,
197.3 ppm; IR (neat): n˜max =3019, 1683, 1605, 1435, 1360, 1264,
1215, 906, 730 cmÀ1
.
128.3, 129.2, 135.0, 137.4, 143.3, 159.1, 170.1 ppm; IR (neat): n˜max
2945, 2869, 1728, 1607, 1574, 1499, 1435, 1296 cmÀ1
=
1
Compound (Z)-1e: Pale yellow oil; H NMR (300 MHz, CDCl3): d=
2.63 (s, 3H), 3.62 (s, 3H), 6.44 (s, 1H), 7.22–7.42 (m, 7H), 8.00 ppm
(d, J=8.6 Hz, 2H); 13C NMR (75 MHz, CDCl3): d=26.5, 51.3, 117.3,
127.9, 128.0, 128.5, 129.2, 129.7, 136.5, 139.7, 143.9, 156.0, 166.0,
197.6 ppm; IR (neat): n˜max =3020, 1682, 1604, 1434, 1360, 1267,
1215, 1169, 908, 754 cmÀ1; HRMS (ESI): m/z calcd for C18H16O3 [M+
Na]+: 303.0997; found: 303.1020.
Compound (E)-1 f: Colorless crystals; m.p. 94–988C; 1H NMR
(300 MHz, CDCl3): d=2.06 (s, 3H), 3.66 (s, 3H), 6.00 (s, 1H), 7.11–
7.37 ppm (m, 9H); 13C NMR (75 MHz, CDCl3): d=20.2, 51.2, 119.4,
125.6, 127.6, 128.4, 129.1, 129.5, 130.6, 135.9, 138.5, 141.9, 157.1,
.
1
Compound (E)-2d: Colorless crystals; m.p. 68–698C; H NMR: d=
2.33 (s, 3H), 3.78 (s, 3H), 6.91–7.03 (m, 4H), 7.07–7.17 ppm (m, 5H);
13C NMR: d=22.9, 52.0, 127.0, 127.9, 128.1, 129.7, 129.8, 132.2,
132.8, 136.8, 140.2, 143.0, 169.5 ppm; IR (neat): n˜max =2950, 1718,
1594, 1485, 1433, 1317, 1245, 1203 cmÀ1; HRMS (ESI): m/z calcd for
C17H15O2Cl [M+Na]+: 309.0658; found: 309.0663.
1
Compound (Z)-2d: Colorless crystals; m.p. 70–718C; H NMR: d=
2.01 (s, 3H), 3.46 (s, 3H), 7.22–7.45 ppm (m, 9H); 13C NMR: d=22.3,
51.8, 127.7, 128.3, 128.4, 128.4, 129.1, 133.0, 133.4, 136.8, 141.3,
Chem. Eur. J. 2015, 21, 5934 – 5945
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142.8, 169.4 ppm; IR (neat): n˜max =2950, 1717, 1634, 1483, 1432,
1296, 1258, 1208 cmÀ1
145.0, 169.2 ppm; IR (neat): n˜max =2951, 1697, 1491, 1428, 1319,
1214, 1088, 1008 cmÀ1; HRMS (ESI): m/z calcd for C17H15O2Cl [M+
Na]+: 309.0658; found: 309.0654.
.
1
Compound (E)-2e: Pale yellow oil; H NMR: d=2.37 (s, 3H), 3.76
(s, 3H), 6.55–6.63 (m, 1H), 6.90–6.98 (m, 1H), 6.98–7.05 (m, 1H),
7.06–7.14 (m, 2H), 7.16–7.25 ppm (m, 3H); 13C NMR: d=20.9, 51.8,
110.3, 126.0, 127.5, 128.4, 129.6, 130.4, 135.5, 138.1, 142.0, 142.4,
169.3 ppm; IR (neat): n˜max =3138, 3023, 2950, 1710, 1597, 1433,
Compound (Z)-2i-x: Colorless crystals; m.p. 107–1088C; 1H NMR:
d=2.11 (s, 3H), 3.45 (s, 3H), 7.27–7.51 (10H, m), 7.58–7.70 ppm (m,
4H); 13C NMR: d=22.4, 51.7, 126.9, 127.0, 127.4, 127.6, 128.2, 128.8,
129.7, 132.2, 136.1, 140.4, 140.6, 142.9, 144.1, 169.8 ppm; IR (neat):
n˜max =3028, 2955, 1726, 1600, 1488, 1434, 1259, 1217 cmÀ1
.
1321, 1205 cmÀ1
.
1
Compound (E)-9 (Scheme 3, [a]): TsCl (858 mg, 4.50 mmol) in DMA
(3.0 mL) was added to a stirred solution of b-ketoester 8a (538 mg,
3.00 mmol), NMI (369 mg, 4.50 mmol), and Et3N (455 mg,
4.50 mmol) in DMA (3.0 mL) at 20–258C and the mixture was
stirred at the same temperature for 1 h. Water was added to the
mixture, which was extracted twice with Et2O. The combined or-
ganic phase was washed three times with water and brine, dried
(Na2SO4), and concentrated. The obtained crude product (96%,
E/Z=75:25) was purified by column chromatography on silica gel
(hexane/2-propanol=10:1) to give the desired product (E)-9
Compound (Z)-2e: Pale yellow oil; H NMR: d=1.98 (s, 3H), 3.67
(s, 3H), 6.43–6.48 (m, 1H), 7.28–7.44 (m, 6H), 7.52–7.57 ppm (m,
1H); 13C NMR: d=20.1, 52.0, 109.5, 126.0, 127.6, 128.3, 129.0, 130.8,
131.4, 136.6, 140.6, 142.9, 170.4 ppm; IR (neat): n˜max =2997, 2949,
1716, 1634, 1493, 1434, 1379, 1207 cmÀ1
.
1
Compound (E)-2 f: Pale yellow oil; H NMR: d=2.34 (s, 3H), 3.73 (s,
3H), 5.62–5.67 (m, 1H), 7.08–7.14 (m, 2H), 7.16–7.24 (m, 2H), 7.27–
7.37 ppm (m, 3H); 13C NMR: d=22.5, 51.8, 124.2, 124.4, 127.1,
128.0, 128.1, 129.5, 131.2, 137.6, 138.5, 141.7, 169.6 ppm; IR (neat):
n˜max =3139, 3026, 2952, 1710, 1608, 1504, 1433, 1205 cmÀ1; HRMS
(ESI): m/z calcd for C15H14O2S [M+Na]+: 281.0612; found: 281.0603.
1
(660 mg, 66%) as a red oil. H NMR (300 MHz, CDCl3): d=2.43 (s,
3H), 3.65 (s, 3H), 6.18 (s, 1H), 7.22 (dd, J=4.5, 7.9 Hz, 1H), 7.28 (d,
J=7.2 Hz 2H,), 7.64–7.73 (m, 3H), 8.50 (d, J=1.7 Hz, 1H), 8.56 ppm
(dd, J=1.4, 4.8 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=21.7, 51.9,
113.1, 122.4, 128.2, 130.0, 132.5, 136.5, 146.0, 149.7, 150.9, 156.3,
164.5 ppm; IR (neat): n˜max =3036, 2953, 1729, 1650, 1597, 1381,
1
Compound (Z)-2 f: Pale yellow oil; H NMR: d=2.02 (s, 3H), 3.56 (s,
3H), 7.09–7.14 (m, 1H), 7.27–7.44 ppm (m, 7H); 13C NMR: d=21.2,
51.8, 122.4, 125.3, 126.9, 127.6, 128.3, 129.0, 132.3, 136.1, 136.7,
142.4, 170.2 ppm; IR (neat): n˜max =2993, 2946, 1715, 1623, 1492,
1433, 1299, 1211 cmÀ1
.
1231, 1194, 1051, 820, 709 cmÀ1
.
1
Compound (E)-2g: Pale yellow oil; H NMR: d=2.23 (s, 3H), 2.33
(s, 3H), 3.78 (s, 3H), 6.83–6.95 (m, 4H), 6.98–7.08 (m, 2H), 7.10–
7.20 ppm (m, 2H); 13C NMR: d=21.1, 23.2, 51.9, 126.9, 127.9, 128.4,
128.5, 129.1, 129.6, 134.1, 136.5, 142.0, 143.6, 170.1 ppm; IR (neat):
n˜max =3023, 1717, 1636, 1509, 1491, 1435, 1375, 1250 cmÀ1; HRMS
(ESI): m/z calcd for C18H18O2 [M+Na]+: 289.1204; found: 289.1210.
Compound (Z)-9 (Scheme 3, [b]): TsCl (191 mg, 1.00 mmol) in
CH2Cl2 (0.5 mL) was added to a stirred solution of b-ketoester 8a
(90 mg, 0.50 mmol), NaOH (30 mg, 1.00 mmol), and NMI (82 mg,
0.75 mmol) in CH2Cl2 (0.5 mL) at 20–258C and the mixture was
stirred at the same temperature for 1 h. Water was added to the
mixture, which was extracted twice with AcOEt. The combined or-
ganic phase was washed with brine, dried (Na2SO4), and concen-
trated. The obtained crude product was purified by column chro-
matography on silica gel (hexane/AcOEt=2:1) to give the desired
product (Z)-9 (135 mg, 81%, E/Z=8:92), which was washed with
hexane to yield pure (Z)-9 (110 mg, 66%) as yellow crystals. M.p.
87–898C; 1H NMR (300 MHz, CDCl3): d=2.43 (s, 3H), 3.71 (s, 3H),
6.16 (s, 1H), 7.23 (dd, J=4.8, 8.6 Hz, 1H), 7.27 (d, J=8.3 Hz, 2H),
7.72–7.79 (m, 3H), 8.59 (dd, J=1.7, 4.8 Hz, 1H), 8.68 ppm (d, J=
2.1 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=21.6, 51.8, 111.9, 123.1,
128.4, 129.3, 129.7, 132.9, 134.2, 145.7, 147.6, 151.3, 152.8,
163.2 ppm; IR (neat): n˜max =3087, 2953, 1728, 1643, 1380, 1316,
1269, 1181, 1162, 994, 933, 838, 672 cmÀ1; HRMS (ESI): m/z calcd for
C16H15NO5S [M+Na]+: 356.0569; found: 356.0599.
1
Compound (Z)-2g: Pale yellow oil; H NMR: d=2.05 (s, 3H), 2.33
(s, 3H), 3.42 (s, 3H), 7.04–7.45 ppm (m, 9H); 13C NMR: d=21.2,
22.3, 51.6, 126.9, 127.5, 128.2, 128.5, 129.1, 129.6, 134.2, 137.3,
143.0, 143.5, 169.9 ppm; IR (neat): n˜max =2947, 1719, 1636, 1509,
1491, 1435, 1375, 1252 cmÀ1
.
1
Compound (E)-2h: Pale yellow oil; H NMR: d=2.33 (s, 3H), 3.71
(s, 3H), 3.79 (s, 3H), 6.58–6.68 (m, 2H), 6.85–6.95 (m, 2H), 7.09–
7.22 ppm (m, 2H); 13C NMR: d=23.1, 51.9, 55.0, 113.3, 126.9, 127.9,
128.5, 129.4, 131.0, 131.2, 142.0, 143.2, 158.3, 170.2 ppm; IR (neat):
n˜max =2951, 1719, 1609, 1576, 1509, 1458, 1375, 1248 cmÀ1; HRMS
(ESI): m/z calcd for C18H18O3 [M+Na]+: 305.1154; found: 305.1161.
1
Compound (Z)-2h: Pale yellow oil; H NMR: d=2.06 (s, 3H), 3.42
(s, 3H), 3.84 (s, 3H), 6.87–6.97 (m, 2H), 7.21–7.40 ppm (m, 7H);
13C NMR: d=22.2, 51.6, 55.2, 113.8, 126.9, 127.5, 128.2, 129.4, 130.4,
131.0, 132.2, 143.3, 159.0, 170.0 ppm; IR (neat): n˜max =2951, 1719,
Compound (Z)-10 (Scheme 3, [c]): TsCl (143 mg, 0.750 mmol) in
CH2Cl2 (0.5 mL) was added to a stirred solution of b-ketoester 8b
(129 mg, 0.50 mmol), LiOH (18 mg, 0.75 mmol), and NMI (62 mg,
0.75 mmol) in CH2Cl2 (0.5 mL) at 20–258C and the mixture was
stirred at the same temperature for 2 h. Water was added to the
mixture, which was extracted twice with AcOEt. The combined or-
ganic phase was washed with H2O and brine, dried (Na2SO4), and
concentrated. The obtained crude product was purified by column
chromatography on silica gel (hexane/AcOEt=20:1) to give the de-
sired product (Z)-10 (149 mg, 72%) as colorless crystals. 1H NMR
(300 MHz, CDCl3): d=2.43 (s, 3H), 3.68 (s, 3H), 6.10 (s, 1H), 7.26 (d,
J=8.9 Hz, 2H), 7.29 (d, J=8.6 Hz, 2H), 7.41 (d, J=8.6 Hz, 2H),
7.73 ppm (d, J=8.3 Hz, 2H); 13C NMR (75 MHz, CDCl3): d=21.6,
51.7, 110.7, 125.4, 128.3, 128.5, 129.6, 131.7, 132.1, 133.2, 145.6,
154.6, 163.6 ppm; IR (neat): n˜max =2948, 1733, 1649, 1587, 1484,
1655, 1601, 1541, 1509, 1437, 1250 cmÀ1
.
1
Compound (E)-2i: Pale yellow oil; H NMR d =2.37 (s, 3H), 3.78 (s,
3H), 6.88–6.95 (m, 2H), 6.96–7.03 (m, 2H), 7.03–7.11 (m, 2H), 7.11–
7.21 ppm (m, 3H); 13C NMR: d=23.3, 52.0, 127.2, 128.0, 128.0,
128.3, 130.4, 131.3, 132.7, 135.7, 141.6, 146.0, 169.4 ppm; IR (neat):
n˜max =2949, 1707, 1619, 1591, 1489, 1434, 1251, 1206 cmÀ1
.
1
Compound (E)-2i-x: Colorless oil; H NMR: d=2.38 (s, 3H), 3.82 (s,
3H), 7.03–7.09 (m, 4H), 7.12–7.17 (m, 3H), 7.29–7.42 (m, 4H), 7.49–
7.54 ppm (m, 2H); 13C NMR: d=23.3, 52.0, 126.4, 126.8, 127.1,
127.2, 127.9, 128.4, 128.6, 130.2, 131.3, 136.1, 139.3, 140.4, 141.8,
144.4, 169.9 ppm; IR (neat): n˜max =3028, 2949, 1716, 1487, 1433,
1320, 1246, 1206 cmÀ1; HRMS (ESI): m/z calcd for C23H20O2 [M+Na]+
: 351.1361; found: 351.1375.
1433, 1378, 1188, 1152, 1036, 834, 765, 670 cmÀ1
.
1
Compound (Z)-2i: Colorless crystals; m.p. 115–1168C; H NMR: d=
Compound (E)-10 (Scheme 3, [d]): TsCl (14.3 g, 75 mmol) in DMA
(50 mL) was added to a stirred solution of b-ketoester 8b (12.9 g,
50.0 mmol), NMI (6.2 g, 75 mmol), and Et3N (7.6 g, 75 mmol) in
2.04 (s, 3H), 3.42 (s, 3H), 7.24–7.44 ppm (m, 9H); 13C NMR: d=22.4,
51.7, 126.8, 127.7, 128.2, 128.6, 130.6, 131.3, 133.5, 135.6, 142.6,
Chem. Eur. J. 2015, 21, 5934 – 5945
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5942
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DMA (50 mL) at 20–258C for 0.5 h, and the mixture was stirred at
the same temperature for 1 h. Water was added to the mixture,
and organic layer was separated. The aqueous phase was extracted
twice with Et2O. The combined organic phase was filtered through
a glass filter followed by washing three times with H2O and brine,
dried (Na2SO4), and concentrated. The obtained crude product
(92%, E/Z=67:33) was purified by column chromatography on
silica gel (hexane/AcOEt=20:1) to give the desired product (E)-10
(12.8 g, 62%) as a pale yellow oil. 1H NMR (300 MHz, CDCl3): d=
2.44 (s, 3H), 3.64 (s, 3H), 6.08 (s, 1H), 7.19 (d, J=8.6 Hz, 2H), 7.25
(d, J=7.9 Hz, 2H), 7.38 (d, J=8.3 Hz, 2H), 7.64 ppm (d, J=8.3 Hz,
2H); 13C NMR (75 MHz, CDCl3): d=21.7, 51.8, 112.0, 125.1, 128.2,
129.8, 130.6, 130.8, 131.0, 132.7, 145.8, 158.5, 164.7 ppm; IR (neat):
n˜max =3069, 2952, 2846, 1727, 1644, 1589, 1487, 1379, 1220, 1177,
1033, 836, 754 cmÀ1; HRMS (ESI): m/z calcd for C17H15BrO5S [M+
Na]+: 432.9721; found: 432.9720.
was stirred at the same temperature for 3 h. After cooling, water
was added to the mixture, which was extracted three times with
Et2O. The combined organic phase was washed with brine, dried
(Na2SO4), and concentrated. The obtained crude product was puri-
fied by column chromatography on silica gel (hexane/AcOEt=3:1)
to give the desired product (E)-11 (129 mg, 81%, E/Z=97:3) as
a colorless oil. 1H NMR (300 MHz, CDCl3): d=3.66 (s, 3H), 6.39 (s,
1H), 7.09 (d, J=8.6 Hz, 2H), 7.27 (ddd, J=0.7, 4.8, 7.9 Hz, 1H),
7.48–7.58 (m, 3H), 8.58 (d, J=2.1 Hz, 1H), 8.60 ppm, (dd, J=1.7,
4.8 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=51.5, 118.6, 123.0, 123.2,
130.7, 131.4, 135.5, 136.1, 136.5, 148.9, 150.5, 152.6, 165.6 ppm; IR
(neat): n˜max =3427, 3030, 2949, 2841, 1906, 1722, 1619, 1488, 1434,
1360, 1277, 1165, 1010, 824, 758, 708 cmÀ1
.
(Z)-3-(4-Bromophenyl)-3-(3-pyridinyl)prop-2-en-1-ol[14] (Scheme
3, [i]-(i)): DIBAL (42.4 mL; 1.0m in toluene) was added to a stirred
solution of the ester (Z)-11 (3.36 g, 10.6 mmol) in THF (21.2 mL) at
À788C under an argon atmosphere, and the mixture was stirred at
the same temperature for 0.5 h. MeOH (ca. 30 mL) and a saturated
aqueous solution of Na/K tartrate (ca. 80 mL) were successively
added to the mixture, followed by stirring for 1 h, which was ex-
tracted twice with AcOEt. The organic phase was dried (Na2SO4)
and concentrated. The obtained pale yellow solid was washed
(hexane/Et2O=5/1) to give the desired product (2.42 g, 79%) as
pale yellow crystals. M.p. 123–1248C; 1H NMR (300 MHz, CDCl3):
d=2.00 (brs, 1H), 4.21 (d, J=6.9 Hz, 2H), 6.34 (t, J=6.9 Hz, 1H),
7.08 (d, J=8.6 Hz, 2H), 7.32 (dd, J=4.9, 7.9 Hz, 1H), 7.43 (d, J=
8.6 Hz, 2H), 7.48 (dt, J=7.6, 2.1 Hz, 1H), 8.40 (d, J=1.4 Hz, 1H),
8.58 ppm (dd, J=1.4, 4.8 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=
59.8, 122.0, 123.4, 129.0, 130.7, 131.5, 134.5, 137.5, 138.7, 139.8,
148.6, 149.9 ppm; IR (neat): n˜max =3241, 3038, 2922, 2844, 2669,
1488, 1414, 1028, 804, 718 cmÀ1; HRMS (ESI): m/z calcd for
C14H12BrNO [M+H]+: 290.0181; found: 290.0208.
Compound (Z)-11 (Scheme 3, [e]): A 3m aqueous solution of
K2CO3 (0.25 mL, 0.75 mmol) was added to a stirred suspension of
enol tosylate (E)-9 (83 mg, 0.25 mmol), (p-Br)C6H4B(OH)2 (52 mg,
0.26 mmol), and [Pd(PPh3)2Cl2] (9 mg, 0.01 mmol) in 2-propanol
(0.75 mL) at 60–658C under an argon atmosphere, and the mixture
was stirred at the same temperature for 1 h. After cooling, water
was added to the mixture, which was extracted three times with
Et2O. The combined organic phase was washed with brine, dried
(Na2SO4), and concentrated. The obtained crude product was puri-
fied by column chromatography on silica gel (hexane/AcOEt=3:1)
to give the desired product (Z)-11 (70 mg, 89%, E/Z=2:>98). The
use of [Pd(dppb)Cl2] catalyst instead of [Pd(PPh3)2Cl2] resulted in
35% conversion.
Compound (Z)-11 (Scheme 3, [g]): A 3m aqueous solution of
K2CO3 (13.0 mL, 39 mmol) was added to a stirred suspension of
enol tosylate (Z)-10 (5.35 g, 13.0 mmol), 3-PyB(OH)2 (2.56 g,
21.0 mmol), and [Pd(dppf)Cl2] (476 mg, 0.651 mmol) in 2-propanol
(39.0 mL) at 60–658C under an argon atmosphere, and the mixture
was stirred at the same temperature for 3 h. After cooling, water
was added to the mixture, which was extracted three times with
Et2O. The combined organic phase was washed with brine, dried
(Na2SO4), and concentrated. The obtained crude product was puri-
fied by column chromatography on silica gel (hexane/AcOEt=3:1)
to give the desired product (Z)-11 (3.36 g, 81%, E/Z=2:>98) as
a red oil. 1H NMR (300 MHz, CDCl3): d=3.63 (s, 3H), 6.44 (s, 1H),
7.15 (d, J=8.6 Hz, 2H), 7.34 (dd, J=4.8, 7.9 Hz, 1H), 7.45–7.57 (m,
3H), 8.45 (d, J=2.4 Hz, 1H), 8.64 ppm (dd, J=1.6, 4.8 Hz, 1H);
13C NMR (75 MHz, CDCl3): d=51.5, 118.6, 122.8, 124.4, 129.6, 131.8,
(E)-3-(4-Bromophenyl)-3-(3-pyridinyl)prop-2-en-1-ol
(3b)[14]
(Scheme 3, [j-(i)]): DIBAL (4.0 mL; 1.0m in toluene) was added to
a stirred solution of ester (E)-11 (318 mg, 1.00 mmol) in THF
(2.0 mL) at À788C under an argon atmosphere, and the mixture
was stirred at the same temperature for 0.5 h. MeOH (ca. 3 mL)
and saturated aqueous solution of Na/K tartrate (ca. 8 mL) were
successively added to the mixture followed by stirring for 0.5 h,
which was extracted twice with AcOEt. The organic phase was
dried (Na2SO4) and concentrated. The obtained crude product was
purified by column chromatography on silica gel (hexane/AcOEt=
1:1) to give the desired product (261 mg, 90%) as a colorless solid.
1
M.p. 123–1248C; H NMR (300 MHz, CDCl3): d=2.80 (brs, 1H), 4.24
134.0, 136.5, 138.8, 149.5, 149.6, 152.2, 165.7 ppm; IR (neat): n˜max
3435, 3029, 2949, 1849, 1907, 1720, 1618, 1583, 1272, 1166, 1073,
1009, 826, 752, 713 cmÀ1
=
(d, J=6.9 Hz, 2H), 6.30 (t, J=6.9 Hz, 1H), 7.02 (d, J=8.3 Hz, 2H),
7.24 (dd, J=5.2, 7.9 Hz, 1H), 7.43–7.57 (m, 3H), 8.41–8.64 ppm (m,
2H); 13C NMR (75 MHz, CDCl3): d=60.0, 122.2, 123.3, 130.7, 131.2,
.
131.7, 135.3, 136.7, 137.3, 139.3, 148.0, 148.2 ppm; IR (neat) n˜max
3296, 2875, 1489, 1398, 1010, 822, 717 cmÀ1
=
Compound (E)-11 (Scheme 3, [f]): A 3m aqueous solution of K2CO3
(0.25 mL, 0.75 mmol) was added to a stirred suspension of enol to-
sylate (Z)-9 (83 mg, 0.25 mmol), (p-Br)C6H4B(OH)2 (52 mg,
0.26 mmol), and [Pd(PPh3)2Cl2] (9 mg, 0.01 mmol) in 2-propanol
(0.75 mL) at 60–658C under an argon atmosphere, and the mixture
was stirred at the same temperature for 1 h. After cooling, water
was added to the mixture, which was extracted three times with
Et2O. The combined organic phase was washed with brine, dried
(Na2SO4), and concentrated. The obtained crude product was puri-
fied by column chromatography on silica gel (hexane/AcOEt=3:1)
to give the desired product (E)-11 (63 mg, 79%, E/Z=99:1).
.
Compound (Z)-3[14] (Scheme 3, [i]-(ii)): SOCl2 (0.10 mL, 1.35 mmol)
and DMF (1 drop) were successively added to a stirred solution of
the allyl alcohol (261 mg, 0.900 mmol) in CH2Cl2 (0.9 mL) at 20–
258C, and the mixture was stirred at the same temperature for
10 min. Then, an aqueous solution of Me2NH (0.95 mL, 9.5m) was
added to the mixture followed by stirring for 0.5 h. A saturated
aqueous solution of NaHCO3 was added to the mixture, which was
extracted three times with AcOEt. The organic phase was washed
with brine, dried (Na2SO4), and concentrated. The obtained crude
product was purified by column chromatography on silica gel
(AcOEt/Et3N=10:1) to give the desired product (Z)-3 (260 mg,
91%) as a yellow oil. 1H NMR (300 MHz, CDCl3): d=2.23 (s, 6H),
2.98 (d, J=6.9 Hz, 2H), 6.29 (t, J=6.9 Hz, 1H), 7.09 (d, J=8.6 Hz,
2H), 7.33 (ddd, J=1.0, 4.8, 7.6 Hz, 1H), 7.42 (d, J=8.6 Hz, 2H), 7.46
Compound (E)-11 (Scheme 3, [h]): A 3m aqueous solution of
K2CO3 (0.50 mL, 1.5 mmol) was added to a stirred suspension of
enol tosylate (E)-10 (206 mg, 0.500 mmol), 3-PyB(OH)2 (92 mg,
0.75 mmol), and [Pd(dppf)Cl2] (18 mg, 0.025 mmol) in 2-propanol
(1.5 mL) at 60–658C under an argon atmosphere, and the mixture
Chem. Eur. J. 2015, 21, 5934 – 5945
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5943
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[3] a) Y. Yamamoto, N. Kirai, Y. Harada, Chem. Commun. 2008, 2010; b) N.
Kirai, Y. Yamamoto, Org. Synth. 2010, 87, 53.
[4] a) A. B. Lemay, K. S. Vulic, W. W. Oglivie, J. Org. Chem. 2006, 71, 3615;
b) J. S-Mercier, A. B. Flynn, W. W. Ogilvie, Tetrahedron 2008, 64, 5472.
[5] M. Shindo, Y. Sato, T. Yoshikawa, R. Koretsune, K. Shishido, J. Org. Chem.
2004, 69, 3912.
(dt, J=7.6, 2.1 Hz, 1H), 8.44 (dd, J=0.7, 2.4 Hz, 1H), 8.60 ppm (dd,
J=1.7, 4.8 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=45.3, 58.1, 121.7,
123.2, 128.8, 129.5, 131.4, 134.7, 137.1, 139.2, 140.2, 148.7,
150.5 ppm; IR (neat): n˜max =3457, 3028, 2973, 2941, 2855, 2817,
2768, 1670, 1585, 1488, 1263, 1024, 817, 717 cmÀ1
.
Compound (E)-3[14] (Scheme 3, [j]-(ii)): SOCl2 (0.06 mL, 0.75 mmol)
and DMF (1 drop) were successively added to a stirred solution of
the allyl alcohol (145 mg, 0.500 mmol) in CH2Cl2 (0.5 mL) at 20–
258C, and the mixture was stirred at the same temperature for
10 min. Then, an aqueous solution of Me2NH (0.53 mL, 9.5m) was
added to the mixture followed by stirring for 0.5 h. A saturated
aqueous solution of NaHCO3 was added to the mixture, which was
extracted twice with AcOEt. The organic phase was washed with
brine, dried (Na2SO4), and concentrated. The obtained crude prod-
uct was purified by column chromatography on silica gel (AcOEt/
Et3N=10:1) to give the desired product (E)-3 (144 mg, 91%, E/Z=
92:8) as a yellow oil. 1H NMR (300 MHz, CDCl3): d=2.24 (s, 6H),
3.00 (d, J=6.5 Hz, 2H), 6.25 (t, J=6.5 Hz, 1H), 7.04 (d, J=8.6 Hz,
2H), 7.20 (dd, J=4.8, 7.9 Hz, 1H), 7.46 (dt, J=7.9, 2.1 Hz, 1H), 7.53
(d, J=8.3 Hz, 2H), 8.49 (dd, J=1.7, 4.8 Hz, 1H), 8.53 ppm (d, J=
1.7 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=45.3, 58.0, 121.7, 122.9,
129.3, 131.3, 131.5, 134.3, 137.1, 137.3, 139.6, 148.3, 148.5 ppm; IR
(neat): n˜max =3394, 3027, 2971, 2940, 2854, 2817, 2768, 1669, 1567,
[6] a) H. Nakatsuji, K. Ueno, T. Misaki, Y. Tanabe, Org. Lett. 2008, 10, 2131;
b) H. Nakatsuji, H. Nishikado, K. Ueno, Y. Tanabe, Org. Lett. 2009, 11,
4258; c) H. Nishikado, H. Nakatsuji, K. Ueno, R. Nagase, Y. Tanabe, Synlett
2010, 2078.
[7] a) A. Coppen, V. A. Rama Rao, C. Swade, K. Wood, Psychopharmacology
1979, 63, 125; b) A. Coppen, V. A. Rama Rao, C. Swade, K. Wood, Psycho-
pharmacology 1979, 63, 199.
[8] J. M. Baxter, D. Steinhuebel, M. Palucki, I. W. Davies, Org. Lett. 2005, 7,
215; stereocomplementary Ts2 O–Et3N or LDA method. TsCl is ca.1/10
more inexpensive than Ts2 O.
[9] An example in which the use of TsCl caused a-chlorination as the side
reaction, see: A. Klapars, K. R. Campos, C.-y. Chen, R. P. Volante, Org.
Lett. 2005, 7, 1185.
[10] For an application to the stereoselective synthesis of Juvenile hor-
mones, see: A. Manabe, Y. Ohfune, T. Shinada, Synlett 2012, 23, 1213;.
[11] A computer-assisted conformation analysis, exemplified by 5a, supports
this speculation [MM2 force field, ChemBio3D Ultra Ver. 14.0 Perkin-
Elmer, Inc.: Waltham, USA]. 1) as expected, the total energy of (E)-5a
was more thermodynamically stable because it was about 16.1 kcal
molÀ1 smaller than that of (Z)-5a. 2) The conjugated system in (Z)-5a
was normally in the plane, whereas that of (E)-5a was considerably
twisted from the plane probably due to stereocongestion between ÀPh
and ÀCO2Me groups; see the examples below: (E)-Enol tosylate 5a:
non-1,4 van der Waals (VDW): À0.0528; 1,4 VDW: 20.5307; dipole/
1487, 1412, 1262, 1174, 1011, 825, 732 cmÀ1
.
Acknowledgements
dipole: 25.0328; total energy: 226.9997 kcalmolÀ1
.
(Z)-Enol
tosylate 5a: non-1,4 VDW: 0.8225; 1,4 VDW: 20.5523; dipole/dipole:
21.6711; total energy: 210.9178 kcalmolÀ1
This research was partially supported by Grant-in-Aids for Sci-
entific Research on Basic Areas (B) “18350056”, Priority Areas
(A) “17035087” and “18037068”, and Exploratory Research
“17655045” from the Ministry of Education, Culture, Sports, Sci-
ence and Technology (MEXT). We thank Dr. Yasutaka Takada
(Nissan Chemical Industries Ltd.) for his helpful discussions
throughout this study.
.
Keywords: cross-coupling · esters · enols · parallel synthesis ·
synthesis design
[1] For representative examples, see: a) M. T. Smith, J. March, Advanced Or-
ganic Chemistry, 6th ed., Wiley, New York, 2007, p. 792; b) L. Kürti, B.
Czakó, Strategic Applications of Named Reactions in Organic Synthesis,
Elsevier, Burlington, 2005, p. 196; c) R. F. Heck, Palladium Reagents in Or-
ganic Syntheses, Vol. 27, Academic Press, Orlando, 1982, p. 345; d) A. de
Meijere, F. E. Meyer, Angew. Chem. Int. Ed. Engl. 1994, 33, 2379; Angew.
Chem. 1994, 106, 2473; e) J. Tsuji, Palladium Reagents and Catalysts; In-
novation in Organic Synthesis, Wiley, Chichester, 1995; f) J. J. Li, Name
Reactions, 3rd ed., Springer, Berlin, 2006; for moderate to good E/Z se-
lectivity for the preparation of 1, see: g) M. M-Manas, M. PØrez, R. Pleix-
ats, Tetrahedron Lett. 1996, 37, 7449; for phosphane-free catalysis for
the preparation of trisubstituted a,b-unsaturated esters four examples
are listed, see: h) C. Gürtler, S. L. Buchwald, Chem. Eur. J. 1999, 5, 3107;
for the reaction with enol tosylates of cyclohexane-1,3-diones, see: i) X.
Fu, S. Zhang, J. Yin, T. L. McAllister, S. A. Jiang, C.-H. Tann, T. K. Thiruven-
gadam, F. Zhang, Tetrahedron Lett. 2002, 43, 573; for phosphane-free
catalysis with good to excellent E/Z selectivity for the preparation of 1,
see: j) G. Battistuzzi, S. Cacchi, G. Fabrizi, Synlett 2002, 3, 0439; for the
reaction of a,b-unsaturated enol tosylates or mesylates with electron-
rich olefins, see: k) A. L. Hansen, T. Skrydstrup, Org. Lett. 2005, 7, 5585;
for a related Heck reaction with vinyl tosylates and phosphates, see:
l) A. L. Hansen, J.-P. Ebran, M. Ahlquist, P. Norrby, T. Skrydstrup, Angew.
Chem. Int. Ed. 2006, 45, 3349; Angew. Chem. 2006, 118, 3427.
[12] For examples of cross-couplings with enol tosylates and phosphates,
see: A. T. Lindhardt, T. Skrydstrup, Chem. Eur. J. 2008, 14, 8756, and rele-
vant references cited therein.
[13] J.-E. Bäckvall, R. E. Nordberg, J.-E. Nystrçm, T. Hçgberg, B. Ulff, J. Org.
Chem. 1981, 46, 3479.
[14] T. Hçgberg, B. Ulff, J. Org. Chem. 1984, 49, 4209.
[15] T. E. Barder, S. D. Walker, J. R. Martinelli, S. L. Buchwald, J. Am. Chem. Soc.
2005, 127, 4685.
[16] a) W. Tang, W. Wang, Y. Chi, X. Zhang, Angew. Chem. Int. Ed. 2003, 42,
3509; Angew. Chem. 2003, 115, 3633; b) H.-J. Zheng, W.-B. Chen, Z.-J.
Wu, J.-G. Deng, W.-Q. Lin, W.-C. Yuan, X.-M. Zhang, Chem. Eur. J. 2008,
14, 9864.
[17] T. Tsuda, T. Yoshida, T. Saegusa, J. Org. Chem. 1988, 53, 607.
[18] H. Tomioka, N. Ichikawa, H. Murata, J. Chem. Soc. Chem. Commun. 1992,
193.
[2] Z. He, S. Kirchberg, R. Frçhlich, A. Studer, Angew. Chem. Int. Ed. 2012,
51, 3699; Angew. Chem. 2012, 124, 3759.
Chem. Eur. J. 2015, 21, 5934 – 5945
www.chemeurj.org
5944
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Full Paper
[19] a) J. W. J. F. Thuring, A. A. M. A. van Gaal, S. J. Hornes, M. M. de Kok,
G. H. L. Nefkens, B. Zwanenburg, J. Chem. Soc., Perkin Trans. 1 1997, 5,
767; b) M. W. Gittos, J. W. James, L. F. Wiggins, Br. Pat., 1 088 846, 1967;
[Chem. Abstr. 1968, 68, 105193x].
[21] H. Tomioka, N. Hayashi, T. Asano, Y. Izawa, Bull. Chem. Soc. Jpn. 1983, 56,
758.
Received: September 5, 2015
Published online on February 27, 2015
[20] V. A. Nikolaev, V. V. Popik, Tetrahedron Lett. 1992, 33, 4483.
Chem. Eur. J. 2015, 21, 5934 – 5945
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